MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate various physiological pathways such as cellular differentiation and proliferation via gene silencing. More specifically, they bind to complementary sequences in target mRNAs and suppress target gene expression.
Alterations in miRNA expression are known to play a critical role in cancer initiation, progression and metastasis (Calin and Croce, 2006; Ma et al., 2007). The robust connection between miRNAs and tumorigenesis is emphasized by the differential expression profiles of miRNAs from healthy tissue across cancers (Ambros, 2004; Bagga and Pasquinelli, 2006; Bartel, 2004). Several miRNAs have been found to be aberrantly expressed in solid tumors as determined by high throughput microarray techniques. In addition, recent evidence indicates that miRNAs might also function as tumor suppressors or activators. Examples include miR-127, and miR-15a/miR-16-1, which target BCL6 and BCL2 anti-apoptotic genes, respectively, and the let-7 family members, which target the Ras oncogenes (Esquela-Kerscher and Slack, 2006; Slack and Weidhaas, 2006). Further, impaired miRNA regulatory network is known to be one of the key mechanisms in brain tumor pathogenesis (Bottoni et al., 2005; Chan et al., 2005).
Malignant gliomas account for approximately 70% of the 22,500 new cases of malignant primary brain tumors that are diagnosed in adults in the United States each year. Malignant gliomas (MG) comprise of grade-III anaplastic astrocytoma and grade-IV glioblastoma multiforme (GBM) lesions that are highly invasive and display histological evidence of malignancy. GBM is a lethal intracranial malignancy with a median survival of less than 12 months (Legler et al., 1999). Composed of a heterogeneous mixture of poorly differentiated neoplastic astrocytes, malignant gliomas primarily affect adults, and preferentially occur in the cerebral hemispheres. Treatment of malignant gliomas is palliative and includes surgery, radiotherapy, and chemotherapy and frequently recur after radiation as focal masses (Garden et al., 1991).
Despite the recent advances in malignant glioma treatment, patients relapse after an initially favorable response to therapies. This is potentially due to a sub-population of cells with tumorigenic potential that are intrinsically resistant to therapy. These cells, referred to as tumor-initiating “stem cells” or cancer stem cells, were identified in a variety of solid tumors including brain tumors (Galli et al., 2004; Hemmati et al., 2003; Singh et al., 2004). This cellular fraction of the tumors is capable of initiating tumors similar to the parental tumor when transplanted into a secondary site (Reya et al., 2001).
It has been found that a malignant glioma is a heterogeneous tumor composed of a small portion of tumor-initiating cells, i.e., glioma stem cells (GSCs). GSCs are phenotypically similar to normal neural stem cells (NSCs). They express CD133 and Nestin, which are characteristic marks for NSCs. Like NSCs, GSCs also possess the self-renewal potential. On the other hand, GSCs have the potential to recapitulate original polyclonal tumors when xeno-grafted to nude mice. They are chemo-resistant and radiation-resistant and therefore responsible for tumor progression and recurrence after conventional therapy.
Altered expression (e.g., reduced/loss-of expression) of a miRNA may lead to aberrant expression of its target proteins, resulting in altered phenotype. For example, overexpression of miR-34a inhibits proliferation, disrupts tumorsphere formation, or induces differentiation of GSCs, but fails to eliminate GSCs (Guessous et al., 2010; Li et al., 2009).